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WO1990008187A1 - Proteine cd2 soluble a deux domaines - Google Patents

Proteine cd2 soluble a deux domaines Download PDF

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Publication number
WO1990008187A1
WO1990008187A1 PCT/US1989/000218 US8900218W WO9008187A1 WO 1990008187 A1 WO1990008187 A1 WO 1990008187A1 US 8900218 W US8900218 W US 8900218W WO 9008187 A1 WO9008187 A1 WO 9008187A1
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WIPO (PCT)
Prior art keywords
lys
thr
asp
leu
peptide
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Ceased
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PCT/US1989/000218
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English (en)
Inventor
Ellis L. Reinherz
Peter H. Sayre
Rebecca E. Hussey
Hsiu-Ching Chang
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Dana Farber Cancer Institute Inc
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Dana Farber Cancer Institute Inc
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Priority to PCT/US1989/000218 priority Critical patent/WO1990008187A1/fr
Publication of WO1990008187A1 publication Critical patent/WO1990008187A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70507—CD2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the human CD2 (T11) molecule is a 50KD surface glycoprotein expressed on >95% of thymocytes and virtual ly all peripheral T lymphocytes which
  • CD2 Crohn's disease 2019
  • TUTS TUTS
  • CD2 cDNA clones predict a cleaved signal peptide of 24 amino acid residues, an extracellular segment of 185 residues, a transmembrane domain of 25 residues and a cytoplasmic region of 117 residues (Sayre, P.H., et al., Proc. Natl. Acad. Sci. USA 84:2941-2945 (1987); Sewell, W.A., et al., Proc. Natl. Acad. Sci. USA 83:8718-8722 (1986); Seed, B. and A. Aruffo, Proc. Natl. Acad. Sci. USA
  • This invention pertains to a soluble peptide having a lymphocyte function-associated antigen 3 (LFA-3) binding domain and antigenic epitopes recognized by antibodies raised against native surface CD2 on resting T lymphocytes.
  • the soluble peptide is capable of forming at least two intramolecular disulfide bonds and binds the surfacebound CD2 legand, LFA-3.
  • the soluble peptides of this invention exist as monomers in an aqueous medium.
  • the soluble peptides have an amino acid sequence encoded by the two extracellular segment exons of the gene encoding human CD2 glycoprotein.
  • the soluble peptides have about 182 amino acid residues encoded by the two extracellular segment exons of the gene encoding human CD2 glycoprotein.
  • Soluble peptides of this invention can be made by enzymatic fragmentation, peptide synthesis, or recombinant DNA technology. They can be used to block T cell function which is dependent upon antigen activation.
  • Figure 1 shows the amino acid sequence and exon organization of human CD2.
  • Figure la shows the DNA sequence of human CD2 glycoprotein.
  • Figure 2 shows the structure of recombinant soluble T11 ex2 , native CD2 and its genomic
  • Figure 3 shows the construction of expression plasmid for production of the CD2 external segment molecule T11 ex2 .
  • Figure 4 shows SDS-PAGE analysis of purified, radioiodinated and endoglyos idase digested T11 ex2 .
  • Figure 5 shows equilibrium sedimentation data
  • Figure 6 shows the circular dichroism spectra of T11 ex2 .
  • Figure 7 shows the competitive inhibition of radioiodinated T11 ex2 binding of JY cells.
  • Figure 8 shows the saturation binding of T11 ex2 . to JY cells and Scatchard analysis.
  • This invention pertains to a soluble peptide having a lymphocyte function-associated antigen 3 (LFA-3) binding domain and antigenic epitopes
  • the soluble peptide is capable of forming at least two intramolecular disulfide bonds and binds the surface ⁇ bound CD2 ligand, LFA-3.
  • the antigenic epitopes which are localized on the peptide are T11 1 , T11 2 and T11 3 .
  • the soluble peptides are further capable of inhibiting CD2-mediated T cell activation and are soluble in aqueous medium and exist as monomers in the same.
  • the soluble peptides have an amino acid sequence encoded by the two extracellular segment exons of the gene encoding human CD2
  • the soluble peptides are capable of binding the surface-bound CD2 ligand, LFA-3, and can react with antibodies raised against native CD2 on the surface of human T cells.
  • the soluble peptides are further capable of inhibiting CD2-mediated T cell activation.
  • the peptides exist as monomers in an aqueous medium.
  • the soluble peptide comprises about 182 amino acid residues encoded by the two extracellular segment exons of the gene encoding human CD2 glycoprotein.
  • the soluble peptide is monomeric in aqueous medium and comprises four cysteine residues located in the carboxy-terminal region of the amino acid sequence.
  • the peptide is capable of forming at least two sets of intramolecular disulfide bonds between the amino-terminal cysteines and the carboxy-terminal cysteines.
  • the peptide has the
  • the soluble peptide of about 182 amino acid residues in length has an LFA-3 binding domain and comprises the antigenic epitopes T11 1 , T11 2 and T11 3 which are localized on the soluble peptide.
  • the epitopes, which are localized on this peptide are antigenic determinants which are recognized by antibodies against the native surface CD2 structure on resting T lymphocytes.
  • the peptides of this invention can be used to inhibit CD2-mediated T cell
  • amino acid sequence corresponds with a portion of the naturally occurring extracellular domain of CD2 that is capable of binding LFA-3, inhibiting CD2-mediated T cell activation and reacting with antibodies raised against native CD2 on the surface of human T cells.
  • the peptide structure can be modified by deletions, additions, inversions, insertions or substitutions of one or more amino acid residues in the sequence to yield peptides having the characteristics of the peptides of this invention. All such modifications of the above amino acid sequence are embraced by this invention without essentially detracting from the properties of the peptide, i.e., the capacity of the peptide to bind LFA-3, inhibit CD2-mediated T cell activation and react with antibodies raised against native CD2 on the surface of human T cells.
  • the soluble peptides of this invention carry epitopes recognized by antibodies against native surface CD2 structure on resting T lymphocytes and interacts specifically with the surface-bound CD2 ligand, LFA-3. Additionally, the soluble peptide exists as a monomer in aqueous medium and includes a proteolytically-resistant amino-terminal fragment encoded by the first extracellular segment exon of the gene encoding human CD2 glycoprotein.
  • the proteolytically resistant fragment comprises about 100 amino acid residues which correspond with the amino-terminal portion of the extracellular domain of human CD2 glycoprotein and is capable of
  • the 100 amino acid fragment has been described in U.S.
  • This invention also pertains to an isolated DNA sequence that encodes a soluble monomeric human CD2 peptide having an LFA-3 binding domain and antigenic epitopes recognized by antibodies raised against native CD2 on the surface of human T cells and is capable of forming at least two intramolecular disulfide bonds.
  • the antigenic epitopes are T11 1 , T11 2 and T11 3 .
  • the isolated DNA sequence encodes a soluble peptide having an amino acid sequence encoded by the two extracellular segment exons of the gene encoding the human CD2 glycoprotein.
  • the encoded peptide Is capable of binding LFA-3, inhibiting CD2-mediated T cell activation and reacting with antibodies raised against native CD2.
  • the isolated DNA of the invention encodes the 182 amino acid sequence shown above or substantial coding equivalent thereof.
  • the DNA sequence can be modified by deletion, insertion or substitution of nucleotides to yield peptides which exhibit substantially the same properties of the above peptide of about 182 amino acid residues.
  • DNA sequences of the invention can be made using recombinant DNA technology or chemically synthesized.
  • the DNA sequence for CD2 glycoprotein is shown in Figure la.
  • This invention further pertains to a
  • recombinant expression vector comprising the DNA sequence encoding a soluble, monomeric human CD2 peptide having an LFA-3 binding domain and the antigenic epitopes T11 1 , T11 2 and T11 3 .
  • the expression vector comprises a DNA sequence encoding a soluble CD2 protein encoded by the two extracellular segment exons of the gene encoding human CD2 which is capable of inhibiting CD2-mediated T cell activation and LFA-3 binding.
  • the expression vector is a baculovirus transfer vector and comprises a DNA sequence which encodes a peptide of about 182 amino acid residues as shown above.
  • Other vectors may be used, including prokaryotic and eukaryotic expression systems.
  • Soluble peptides of this invention can be made by enzymatic fragmentation of human CD2 glycoprotein or a portion thereof, by peptide synthesis or recombinant DNA technology.
  • the soluble CD2 peptides will be produced by inserting DNA encoding a peptide sequence which is capable of binding LFA-3 and inhibiting CD2-mediated T cell activation (e.g., CD2 DNA which represents the desired amino acid sequence of the extracellular domain of CD2) into an expression vector.
  • CD2-mediated T cell activation e.g., CD2 DNA which represents the desired amino acid sequence of the extracellular domain of CD2
  • transformed cells is capable of binding LFA-3 and inhibiting CD2 -mediated T cell activation.
  • the soluble peptides can be synthesized directly by procedures of chemical protein synthesis.
  • the above 182 amino acid sequence or modified equivalent thereof can be synthesized by the solid phase procedure of Merrifield.
  • This invention further pertains to a method of inhibiting T cell activation, comprising the step of administering to a patient, a soluble peptide having an LFA-3 binding domain, antigenic epitopes recognized by antibodies raised against native CD2 on the surface of human T cells and is capable of forming at least two intramolecular disulfide bonds.
  • a patient is administered a solution containing a soluble peptide having an amino acid sequence encoded by the two extracellular segment exons of the gene encoding human CD2 glycoprotein.
  • the peptide is capable of binding LFA-3, inhibiting T cell activation and reacting with antibodies raised against the native CD2 protein.
  • the soluble peptide comprises a sequence of about 182 amino acid residues which corresponds with the portion of the extracellular domain of human CD2 glycoprotein or fragment thereof which is capable of binding LFA-3 and inhibiting CD2-mediated T cell activation.
  • the soluble peptide can be administered
  • the soluble CD2 peptides of this invention generally will bind to human lymphocytes and human red blood cells which express a homolgous set of surface structures.
  • the soluble peptides are also capable of competing with the naturally-present CD2 on the surface of a human lymphocyte, thus
  • lymphocyte is a cytolytic cell), or with macrophages having CD2 binding structures which permit the cell-to-cell contact necessary for lymphocyte proliferation.
  • a soluble peptide for the ability to inhibit lymphocyte proliferation, or the cytotoxic effector. function, the soluble peptide is contacted with the lymphocytes prior to stimulation with mitogen, and degree of proliferation is
  • the soluble peptides of this invention can be used in a variety of diagnostic and therapeutic applications in which the CD2 surface glycoprotein Is expressed on the surface of many human T cell malignancies, e.g., T cell leukemias and lymphomas.
  • autoimmune diseases e.g., rheumatoid arthritis and Systemic Lupus Erhthmatosis (SLE) are characterized by the presence in the blood and lymph of large numbers of CD2-bearing T cells. Rapid cell turnover in these disease states can cause the shedding of the CD2 molecule into the bloodstream.
  • the CD2 soluble peptides of this invention can be used as an immunogen to produce polyclonal or monoclonal anti-CD2 antibodies, using conventional techniques. These antibodies can be labeled with any conventional label, e.g., radioisotopes, and used in conventional immunoassay methods to measure serum CD2 levels and thus monitor patients having T cell associated diseases. Particularly sensitive ELISA-type assays will employ two anti-CD2 antibodies, each to a different antigenic determinant on the surface of CD2, in a sandwich format.
  • soluble CD2 peptides compete with the surface-bound CD2 for its ligand on target cells thus dampening immune
  • the soluble peptide admixed with a pharmaceutically acceptable carrier comprises about 182 amino acid residues which correspond to a portion of the extracellular domain of CD2 that is capable of binding LFA-3 and inhibiting CD2-mediated CD2 activation.
  • a soluble CD2 peptide can be administered directly to the site where needed most; for example, a soluble CD2 peptide can be injected directly into the inflammed joint of a human patient suffering from rhematoid arthritis.
  • T11 ex2 as referred to in the
  • Exemplification is defined herein to be a soluble protein having an amino acid sequence encoding the two extracellular segment exons and a codon
  • the plasmid pAc373/T11 ex2 was constructed by digestion of pGEM-4-S1, a pGEM derivative containing a 950 bp fragment of the CD2 cDNA PB2 (Sayre et al., Proc. Natl. Acad. Sci. USA 84:2941-2945 (1987)) with PvuII, which digests the cDNA at nucleotide position 628 near the start of the transmembrane region.
  • PvuII A double-stranded synthetic oligonucleotide linker:
  • SF9 cells was carried out as described (Hussey et al. , Nature 331:78-81 (1988). Metabolically labeled culture supernatants were harvested, microfuged for
  • Proteins were prepared for microsequencing by electrophoresis on 12.5% polyacrylamide gels, followed by electroblotting onto polyvinylidene difluoride membranes according to the method of Matsudaira, J. Biol. Chem. 262:10035-10038 (1987). After visualization with Coomassie blue, stained bands were excised and loaded onto an Applied tomuna.
  • Papain 32 ng was added to 8 ⁇ g samples of T11 ex2 at 0.5 mg/ml in PBS containing 10 mM DTT for an enzyme:protein ratio of 1:250. Samples were incubated at 37°C for 15, 30, 45 or 60 min.
  • Far ultraviolet CD spectra were obtained on an Instruments SA Jobin Yvon circular dichrograph calibrated with (+) 10-camphorsulfonic acid and epiandos terone. Measurements were taken at 25, 50 and 80°C +/-0.1°C in 10 mM sodium phosphate pH 7.2 in a 1 mm cell. All spectra represent an average of 3 to 5 individual spectra with data taken at 0.5 mm intervals using a 10 second response time for each point. Protein concentrations were determined by quantitative amino acid analysis of aliquots taken from the sample ceils.
  • T4 ex1 were added in a final volume of 200 ⁇ l in RPMI
  • Coomassie blue staining of two-fold dilutions of standard and test samples run on the same gel and analyzed by densitometry.
  • concentrations of radiolabelled T11 ex2 (1.31 ⁇ 10 7 cpm/nmole) were added to 2.6 ⁇ 10 6 JY cells in the presence or absence of 50 ⁇ g/ml anti-LFA-3 antibody to determine nonspecific binding. Binding was carried out as above and the dissociation constant determined by Scatchard analysis after subtraction of nonspecific binding determined in the presence of anti-LFA-3.
  • Figure 2 shows a comparison of the 182 extracellular CD2 amino acids comprising T11 ex2 (top) to CD2 protein structure (middle). The positions of cysteine residues (C), carbohydrate addition sites (CHO), the CD2 leader segment (L) and the CD2 transmembrane domain (TM) are indicated.
  • exon 1 corresponds to CD2 amino acid residues -24 to -4, exon 2 to residues -4 to 104, exon 3 to residues 104 to 181, exon 4 to residues 181 to 222, and exon 5 to residues 222 to 327
  • the plasmid pAc373/T11 ex2 was constructed and encodes 182 amino acids of the predicted CD2 external segment including all of the residues derived from the two extracellular exons ( Figure 2) and part of one codon (for Glu-181) and all of a second codon (for Lys-182) derived from the transmembrane domain exon.
  • This construction thus, includes all four extracellular cysteine residues located in domain II of CD2 and thereby avoids problems associated with intermolecular disulfide exchange observed with a previous construction (Richardson, et al._, Proc.
  • Plasmid pAc373/T11 ex2 was used to co-transfect SF9 with AcNPV baculoviral DNA. Recombinant baculovirus, termed T11 ex2 -AcNPV, were selected, purified and used to infect small-scale cultures for
  • T11 ex2 -AcNPV was therefore used to infect liter cultures for the production of large amounts of protein.
  • T11 ex2 protein was purified from infected cell supernatants by affinity chromtography on an anti-T11 column.
  • the construction of expression plasmid for production of the CD2 external segment molecule T11 ex2 is shown in Figure 3.
  • the plasmid pGEM-4-S1 carries a 950 bp fragment of the CD2 cDNA.
  • the cDNA insert was isolated and ligated into the BamHI-digested baculoviral transfer vector pAc373.
  • the resulting plasmid pAc373/T11 ex2 encodes 182 amino acids of the mature CD2 extracellular segment.
  • the promoter for the polyhedrin gene in the pAc373 transfer vector is shown by the black box and the polyhedrin gene is indicated by the open box.
  • the 950 bp CD2 coding fragment in pGEM-4-S1 is shown in a stippled box.
  • the position of the T7 polymerase promoter in the pGEM vector is shown.
  • FIG. 4 shows the purification
  • Lanes a-d contain 1 ⁇ g T11 ex2 purified from large scale cultures of SF9 cells infected with T11 ex2 -AcNPV was analyzed by Coomassie staining on a 12.5% polyacrylamide gel in the presence of 50 mM DTT (lane a) or in nonreducing conditions (lane b). An aliquot of T11 ex2 radioiodinated with solid-phase lac toperoxidase/glucose oxidase was analyzed on the same gel in the presence (lane c) or absence (lane d) of 50 Mm DTT by autoradiography. Lanes e-k contain 1 ⁇ g purified T11 ex2 which was digested with
  • T11 ex2 migrates as a well-demarcated doublet in both reducing and non-reducing conditions in SDS-PAGE ( Figure 4, lanes a and b). Two well-separated bands at 30-31KD are seen in the presence of 50 mM DTT (lane a), which migrate at 27-28KD in the absence of reducing agent (lane b). The clear-cut decrease in electrophoretic mobility after reduction with DTT strongly indicates that T11 ex2 contains intrachain disulfide bridges; it does not form interchain bridges.
  • microsequencing analysis of S-cysteine labeled peptides verifies ⁇ that there are two sets of intrachain disulfide bonds in T11 ex2 between the amino-terminal cysteines and carboxy-terminal cysteines.
  • T11 ex2 exists as a noncovalently linked multimer in aqueous solution. It was subjected to equilibrium sedimentation by the high-speed meniscus depletion method (Yphantis,
  • T11 ex2 exists as a monomer in solution.
  • Figure 5 shows the equilibrium sedimentation analysis as a plot of log (fringe displacement) against square of distance from center of rotation, r 2 .
  • T11 ex2 (0.05%) was analyzed by sedimentation equilibrium on a Beckman model E analytical ultracentrifuge in aqueous solution (PBS) at 30,000 rpm ( ⁇ - 3.142 X 10 3 rad/sec) or in dissociating
  • T11 ex2 The expression of CD2 epitopes was investigated by immunoprecipitation analysis.
  • the T11 ex2 molecule can be immunoprecipitated by both anti-T11 1 and a second monoclonal antibody to a different epitope termed anti-T11 2 .
  • T11 ex2 is not immunoprecipitated by the anti-CD2 antibody, anti-T11 3 , which defines an activation specific epitope on CD2.
  • T11 ex2 was able to Inhibit the binding of anti-TlL-FITC to the T11 3 + Jurkat cell line at a concentration of 10 ⁇ m, implying its presence on T11 ex2 (data not shown). These results also suggest that the affinity of anti-T11 3 for its epitope is low.
  • FIG. 6 shows the circular dichroism spectras of T11 ex2 .
  • Far ultraviolet circular dichroism spectra represent the average of 3-5 individual spectra with data taken at 0.5 nm wavelenght intervals in 10mM sodium phosphate, pH 7.2
  • Thy-1 resembles that for Thy-1 (Campell e t al., Nature 282:341-342 (1979)) which is a well-recognized member of the immunoglobulin superfamily (Williams and Barclay, Annu. Rev. Immmunol. 6:381-405 (1988)) and Is therefore predicted to consist entirely of ⁇ -sheet.
  • the shoulder at 225 nm is absent from the Thy-1 profile.
  • the digitalized absorption data (Table I) were deconvoluted according to the inverse matrix method of Compton and Johnson, Anal. Biochem.
  • T11 ex2 The ability of T11 ex2 to interact with the CD2 ligand expressed on the surface of various cell types was investigated.
  • the antl-T11 1 (3T4-8B5) antibody abrogates rosetting at a concentration as low as 0.007 ⁇ M (Table II). This result suggests that any direct interaction between the soluble T11 ex2 molecule and the CD2 ligand is of relatively low affinity.
  • sheep erythrocytes were
  • Anti-CD2 was the anti-T11 1 antibody of 3T4-8B5. T11 ex2 blocks the binding of anti-LFA-3 monoclonal antibody
  • T11 ex2 clearly inhibits sheep erythrocyte rosetting and blocks the binding of anti-LFA-3 antibody, we determined whether specific, saturable binding of T11 ex2 to human cells bearing LFA-3 could be detected. Two types of binding assays were employed. In the first, increasing amounts of unlabeled T11 ex2 was added to a mixture of the JY B lymphoblastoid cell line plus a constant amount of
  • Figure 7 shows the competitive inhibition of radioiodinated T11 ex2 binding to JY cells. 5 ⁇ 10 cpm radiolabelled T11 ex2 (2.8 ⁇ 10 cpm/nmole) was added at 0.1 ⁇ M to 1.8 ⁇ 10 JY cells overlayed onto
  • T11 ex2 unlabeled T11 ex2 (closed circles) or T4 ex1 as a control (open circles) were added in a final volume of 200 ⁇ l in RPMI 1640/10% FCS. After 1 h
  • binding of radiolabeled T11 ex2 is progessively inhibited by the addition of increasing amounts of unlabeled molecules.
  • Half-maximal inhibition occurs at about 0.5 ⁇ M
  • T11 ex2 a soluble, monomeric extracellular segment CD2 molecule, termed T11 ex2 , carries epitopes recognized by antibodies against the native surface CD2 structure on resting T lymphocytes and interacts specifically with the surface-bound CD2 ligand, LFA-3.
  • carboxy-terminal encoded extracellular domain is labile to papain.
  • the virus, AcNP/T11 ex2 has been deposited at the American Type Culture Collection in Rockville, Maryland on January 19, 1989, and assigned the ATCC Accession Number .

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Abstract

On décrit un peptide CD2 soluble ayant un domaine de liaison LFA-3 (antigène associé à la fonction du lymphocyte) et des épitopes antigéniques reconnus par des anticorps dressés contre le CD2 natif à la surface des cellules T, capable de former au moins deux liaisons disulfures intramoléculaires. Ledit peptide est capable de se lier au LFA-3, d'inhiber l'activation des cellules T induite par CD2 et de réagir avec des anticorps dressés contre le CD2. Le peptide soluble comprend de préférence une séquence d'acides aminés de 182 résidus en longueur que codent deux exons de segment extracellulaire du gène qui code pour la glycoprotéine humaine CD2.
PCT/US1989/000218 1989-01-19 1989-01-19 Proteine cd2 soluble a deux domaines Ceased WO1990008187A1 (fr)

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Cited By (104)

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WO1993006852A3 (fr) * 1991-10-07 1993-07-22 Biogen Inc Procede d'amelioration de la tolerance d'allogreffes ou de xenogreffes par administration d'une proteine de liaison de lfa-3 ou de cd2
AU660981B2 (en) * 1991-03-12 1995-07-13 Astellas Us Llc CD2-binding domain of lymphocyte function associated antigen 3
US5622700A (en) * 1992-08-21 1997-04-22 Genentech, Inc. Method for treating a LFA-1-mediated disorder
WO1997037687A1 (fr) * 1996-04-10 1997-10-16 National Jewish Center For Immunology And Respiratory Medicine Produit et procede nouveaux pour molecules veto des lymphocytes t
AU717753B2 (en) * 1991-10-07 2000-03-30 Astellas Us Llc Methods of improving allograft or xenograft tolerance by administration of an LFA-3 or CD2 binding protein
US6162432A (en) * 1991-10-07 2000-12-19 Biogen, Inc. Method of prophylaxis or treatment of antigen presenting cell driven skin conditions using inhibitors of the CD2/LFA-3 interaction
RU2203319C2 (ru) * 1993-08-02 2003-04-27 Мерк Патент-Гмбх Биспецифическая молекула антитела для лизиса опухолевых клеток, способ получения f(ab') 2 фрагмента биспецифической молекулы антитела, моноклональное антитело (варианты), фармацевтический препарат, фармацевтический набор для лизиса опухолевых клеток (варианты), способ лизиса опухолевых клеток ex vivo при аутогенной трансплантации костного мозга
US6764681B2 (en) 1991-10-07 2004-07-20 Biogen, Inc. Method of prophylaxis or treatment of antigen presenting cell driven skin conditions using inhibitors of the CD2/LFA-3 interaction
WO2006089133A2 (fr) 2005-02-15 2006-08-24 Duke University Anticorps anti-cd19 et leur utilisation en oncologie
CZ298238B6 (cs) * 1998-08-31 2007-08-01 Astellas Us Llc Pouzití CD2 vazebného cinidla pro výrobu léku k modulaci pametových T bunek
EP2050763A2 (fr) 2005-03-10 2009-04-22 Genentech, Inc. Procédés et compositions de modulation d'intégrité vasculaire
EP2052742A1 (fr) 2000-06-20 2009-04-29 Biogen Idec Inc. Traitement de maladies liées aux lymphocytes B telles des tumeurs et des maladies auto-immunes utilisant une combinaison d'anticorps anti-CD20 froid et d'anticorps anti-CD22 radiomarqué
EP2062916A2 (fr) 2003-04-09 2009-05-27 Genentech, Inc. Traitement d'une maladie autoimmune chez un patient dont la réponse à un inhibiteur TNF-Alpha n'est pas adéquate
EP2067486A1 (fr) 2001-01-31 2009-06-10 Biogen Idec Inc. Utilisation d'antagonistes CD23 dans le traitement des troubles neoplasiques
WO2009140684A2 (fr) 2008-05-16 2009-11-19 Genentech, Inc. Utilisation de biomarqueurs pour évaluer le traitement de troubles inflammatoires gastro-intestinaux avec des antagonistes de l'intégrine bêta7
US7662921B2 (en) 2004-05-07 2010-02-16 Astellas Us Llc Methods of treating viral disorders
WO2010042890A2 (fr) 2008-10-10 2010-04-15 Anaphore, Inc. Polypeptides qui se lient à trail-ri et trail-r2
WO2010056804A1 (fr) 2008-11-12 2010-05-20 Medimmune, Llc Formulation d’anticorps
WO2010075249A2 (fr) 2008-12-22 2010-07-01 Genentech, Inc. Méthode de traitement de la polyarthrite rhumatoïde avec des antagonistes de cellules b
EP2221316A1 (fr) 2005-05-05 2010-08-25 Duke University Traitements des maladies auto-immunes par des anticorps anti-cd19
US7858095B2 (en) 2001-07-24 2010-12-28 Astellas Us Llc Method for treating or preventing sclerotic disorders using CD-2 binding agents
WO2011014750A1 (fr) 2009-07-31 2011-02-03 Genentech, Inc. Inhibition de métastase tumorale utilisant des antagonistes de bv8 ou de g-csf
EP2289936A1 (fr) 2002-12-16 2011-03-02 Genentech, Inc. Variantes de l'immunoglobuline et leurs utilisations
WO2011033006A1 (fr) 2009-09-17 2011-03-24 F. Hoffmann-La Roche Ag Méthodes et compositions utilisées à des fins de diagnostic chez les patients atteints du cancer
EP2314318A1 (fr) 2001-01-31 2011-04-27 Biogen Idec Inc. Anticorps CD80 pour utilisation en combinaison avec agents chemothérapeutiques pour le traitement de malignité de cellules B
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